Using FFF Beams to Improve the Therapeutic Ratio of Lung SBRT

Abstract

Aim:

To investigate the extent to which lung stereotactic body radiotherapy (SBRT) treatment plans can be improved by replacing conventional flattening filter (FF) beams with flattening filter-free (FFF) beams.

Material and Methods:

We selected 15 patients who had received SBRT with conventional 6-MV photon beams for early-stage lung cancer. We imported the patients’ treatment plans into the Eclipse 13.6 treatment planning system, in which we configured the AAA dose calculation model using representative beam data for a TrueBeam accelerator operated in 6-MV FFF mode. We then created new treatment plans by replacing the conventional FF beams in the original plans with FFF beams.

Results:

The FFF plans had better target coverage than the original FF plans did. For the planning target volume, FFF plans significantly improved the D₉₈, D₉₅, D₉₀, homogeneity index, and uncomplicated tumor control probability. In most cases, the doses to organs at risk were lower in FFF plans. FFF plans significantly reduced the mean lung dose, V₁₀, V₂₀, V₃₀, and normal tissue complication probability for the total lung and improved the dosimetric indices for the ipsilateral lung. For most patients, FFF beams achieved lower maximum doses to the esophagus, heart, and the spinal cord; and a lower chest wall V₃₀.

Findings:

Compared with FF beams, FFF beams achieved lower doses to organs at risk, especially the lung, without compromising tumor coverage; in fact, FFF beams improved coverage in most cases. Thus, replacing FF beams with FFF beams can achieve a better therapeutic ratio.

Introduction

Research on the technology now known as flattening filter-free (FFF) beams began in earnest in the mid-2000s. Initial studies comprehensively characterized the properties of FFF beams and produced compelling evidence of the potential benefits of the technology for cancer radiotherapy. Soon after the publication of these data, Varian Medical Systems (Palo Alto, CA) released the TrueBeam STx, a linear accelerator capable of delivering FFF beams. In 2011, Hrbacek et al. (1) reported on the commissioning of the first clinically used accelerator of this type operated in the FFF mode. Around the same time, George et al. (2) reviewed prior publications and the data available at that time. The broad clinical implementation of accelerators capable of delivering FFF beams soon followed. The American Association of Physicist in Medicine and The Institute of Physics and Engineering promptly reported much-needed guidelines for the clinical implementation of FFF beams (3,4).

FFF beams are well suited for lung stereotactic body radiotherapy (SBRT) because the treatment typically involves small target volumes and large doses per fraction. Early studies of the use of FFF beams for lung SBRT mainly focused on the feasibility of the approach and its potential to reduce the beam-on time (BOT). For example, Vassiliev et al. (5) reported that differences in doses to the planning target volume (PTV) and to critical structures between FFF plans and plans using the conventional flattened beams (FF) were not clinically or statistically significant. However, the median BOT per field was reduced from 25 s with FF beams to 11 s with FFF beams, a reduction sufficient to facilitate the delivery of breath-hold and gated treatments. Boda-Heggemann et al. (6) also showed that FFF beams convey a BOT benefit. In a treatment planning study of intensity-modulated radiotherapy, in which a dynamic multi-leaf collimator or volumetric modulated arc therapy (VMAT) was used for fluence modulation, they found that 10-MV FFF beams could be delivered in one breath hold, which reduced the overall fraction delivery time from approximately 30 min to 15 min. Similarly, Ong et al. (7) reported a reduction in BOT by a factor of approximately 2 when 10-MV FFF beams were used for Rapid Arc treatments. In addition, Prendergast et al., (8) studying a relatively large cohort of 82 lung SBRT patients, of whom 31 were treated with 10-MV FFF beams, reported that the average treatment time with FFF beams was 11.4 min, whereas that for conventional treatments with FF beams was 21.1 min. The average patient immobilization time for FFF beams (32.9 min) was also shorter than that for FF beams (47.0 min). Finally, Gasic et al., (9) who used FF and FFF beams with energies of 6 and 10 MV to develop four VMAT plans for each of 20 patients with early-stage lung cancer, found that differences in target coverage, conformity, and homogeneity were not significant and that doses to organs at risk (OARs) were “comparable” between the FF and FFF treatment plans. Compared with those for the FF-VMAT plans, the average beam delivery times for the FFF-VMAT plans were reduced by 55.3% (6 MV) and 75.0% (10 MV).

More recent studies (10,11) have primarily focused on the dosimetric characterization of treatment plans. Lu et al. (10) designed VMAT plans using FFF beams for 12 patients with stage I lung cancer using three fractionation schemes (4×12 Gy, 3×18 Gy, and 1×34 Gy). They found that the 6-MV plans had significantly lower doses to all OARs than the 10-MV plans did. Accordingly, the normal tissue complication probabilities (NTCPs) for the lung and chest wall for the 6-MV 4- and 3-fraction plans were approximately 10% lower than those for the 10-MV plans. The mean BOTs for the 6-MV 4-, 3-, and 1-fraction plans, were 2.2, 3.3, and 6.3 min, respectively, whereas those for the 10-MV plans were 1.5, 2.0, and 3.5 min, respectively. Similarly, Tambe et al.,¹¹ comparing 6-MV FFF, 10-MV FFF, and 6-MV FF VMAT plans, reported that 6-MV FFF plans achieved significantly better OAR sparing than 6-MV FF or 10-MV FFF plans did, without significant differences in target volume coverage.

Using Monte Carlo simulations of a dose delivered by seven 6-MV coplanar FF or FFF beams, Vassiliev et al. (12) investigated the impact of tumor size and lung density on the dose distributions in a lung tumor and its vicinity in a virtual thorax phantom at a spatial resolution of 0.5–1 mm. The FFF beams achieved consistent, albeit modest, target dose enhancement. The study also showed that lung density is an important factor that affects dose distribution, especially near the lung-tumor interface.

Pokhrel et al. (13) investigated dosimetric differences between 6-MV FF and FFF VMAT plans for a cohort of 13 patients with early-stage non-small cell lung cancer. The use of 6 MV was based on previous studies (10,11) showing that best OAR sparing was achieved with 6-MV FFF beams.) They found that, for the prescribed dose of 30 Gy in one fraction, FFF beams improved target conformity and lowered doses to OARs. The dose reductions to the lung, heart, esophagus, and ribs were all significant, and the BOT was reduced by a factor of 2.3. Using patient data, they also showed the significant impact of lung density on tumor coverage.

Navarria et al. (14) reported on treatment outcomes for a cohort of 46 patients with inoperable early-stage lung cancer treated with 10-MV FFF VMAT. They compared the dose distributions and treatment outcomes for these patients with those for 86 patients treated with 6-MV FF 3-dimensional conformal radiotherapy. The prescription for all patients was 4×12 Gy. In all cases, an “adequate” dose conformity to the target was achieved. No further data on tumor coverage was reported. Consistent with other studies, a significant reduction in doses to the ipsilateral lung was achieved with FFF beams. No data for other OARs was presented. The BOTs for the FFF and FF plans were 1.5 and 8.3 min, respectively. At 1 year, the local control rate of the FFF arm (100%) was significantly higher than that of the FF arm (92.5%; p=0.03). In the FFF arm, 17.4% of patients had grade 1 or 2 pulmonary toxicity, and 4% had grade 3 pulmonary toxicity. The FF arm had higher rates of grade 1, 2, and 3 toxicity, at 24%, 42%, and 9%, respectively.

The data summarized above demonstrate that lung SBRT with FFF beams is feasible and substantially lowers the BOT. Navarria et al. (14) reported remarkable treatment outcomes with FFF beams, although their study had a short follow-up period. They also reported dosimetric differences between FF and FFF treatment plans only for the lung; therefore, the FFF dose distribution properties responsible for achieving the 100% tumor control rate were unclear. Only Pokhrel et al. (13) performed a detailed dosimetric comparison of FF and FFF treatments. Additional dosimetric comparisons of FF and FFF treatments are needed to determine the extent to which FFF beams can improve the therapeutic ratio of lung SBRT. Our study provides data that complement those reported by Pokhrel et al. (13). We used a different treatment technique, static beams, and compared different dosimetric indices, covering all indices for which treatment planning goals are specified in current directives to guide routine planning.

Methods and Materials

The study was approved by the Institutional Review Board. Fifteen patients who previously received SBRT for early-stage lung cancer at our institution were selected for this study. The cohort size was chosen based on preliminary estimates of tumor control probabilities (TCPs). The patients’ characteristics are summarized in Table 1. The table includes the average ipsilateral lung density, derived using the method described by Pokhrel et al. (13), as well as the average chest wall thickness, calculated as the average of all wall thicknesses measured along the central axis of each beam. All treatments used conventional 6-MV FF photon beams. We imported the original treatment plans into Eclipse 13.6 (Varian Medical Systems). The analytical anisotropic algorithm dose calculation model was configured using representative beam data for a TrueBeam accelerator operated in 6-MV FFF mode. After replacing conventional FF beams with FFF beams of the same nominal energy (6 MV), we re-optimized all the plans without changing the beam setup. The optimization strategy was to match the PTV coverage, verify that gross tumor volume (GTV) coverage was not compromised, and attempt to lower the dose to OARs, starting with the lung. In most cases, FFF beams improved the target coverage, although this was not an explicit optimization goal. Other OARs were the esophagus, heart, spinal cord, and chest wall.

Table 1.

Patient characteristics.

Patient	Tumor location	Fractionation	GTV, cm3	PTV, cm3	Average ipsilateral lung density, g/cm3	Average chest wall thickness, cm
1	upper right	4×12.5 Gy	1.8	35.6	0.283	5.81
2	upper left	4×12.5 Gy	8.1	30.6	0.350	6.81
3	middle right	7×9 Gy	35.6	86.4	0.335	6.86
4	middle right	7×10 Gy	53.4	117.6	0.281	3.77
5	upper right	7×10 Gy	99	280.1	0.222	7.55
6	middle right	4×12.5 Gy	4.8	19.6	0.269	4.67
7	upper right	7×10 Gy	66.4	138	0.240	5.63
8	lower left	7×10 Gy	60	229	0.355	6.68
9	upper right	4×12.5 Gy	5.4	56.7	0.314	6.98
10	lower left	4×12.5 Gy	5	60.9	0.269	3.83
11	middle right	4×12.5 Gy	1.8	34.5	0.240	7.23
12	middle left	4×12.5 Gy	15.3	41.1	0.343	6.13
13	upper right	4×12.5 Gy	0.6	5.5	0.249	8.02
14	upper right	4×12.5 Gy	1.4	9.2	0.252	8.33
15	middle right	4×12.5 Gy	9	70.3	0.407	8.82
	Median (range)		8.1 (0.6, 99)	56.7 (5.5, 280)	0.281 (0.222, 0.407)	6.81 (3.77, 8.82)

Abbreviations: GTV, gross tumor volume; PTV, planning target volume

For each FF or FFF treatment plan, we calculated multiple dose-volume histogram indices characterizing target coverage and doses to the OARs. We also calculated the homogeneity index (HI), defined as HI=(D_2%-D_98%)/D_50%, (15) and the conformity index (CI), which is the ratio of volume receiving at least the prescription dose, V(R_x), to the PTV.

Tumor control probability

To calculate the TCP, we followed the method described by Chetty et al. (16). The following equations for the TCP were derived by Webb and Nahum (17) and Guckenberger et al. (18) for a single fraction. We modified them to account for the effect of fractionation. Let α and β be parameters of the linear-quadratic model of cell survival, M the total number of voxels in the target volume, N_i⁽⁰⁾ the initial number of clonogenic cells in the i-th voxel, D_i the total dose delivered to the i-th voxel, and F_x the number of fractions. For an individual patient with a given α, the TCP is $TCP(\alpha )={\prod }_{i=1}^M\text{exp}\left\{-N_i^{(0)}\cdot exp\left[-\alpha D_i-\beta F_x{\left(D_i/F_x\right)}^2\right]\right\}$

For a population, it is assumed that α is normally distributed with parameters (α_av, σ_α).

Therefore, the average TCP for the population is:

$$TCP=\frac{1}{\sqrt{2\pi {\sigma }_{\alpha }^2}}\underset{-\infty }{\overset{+\infty }{\int }}TCP(\alpha )\cdot exp\left[-\frac{{\left(\alpha -{\alpha }_{av}\right)}^2}{2{\sigma }_{\alpha }^2}\right]d\alpha$$

The model parameters are the same as ose given by Chetty et al. (16): α_av= 0.292 Gy⁻¹, σ_α=0.037 Gy⁻¹, β = α_av/10 Gy, and the initial number density of clonogenic cells is 10⁷ cm⁻³. The number of cells in a voxel N_i⁽⁰⁾ is the product of the number density and the voxel volume. The voxel volume and dose to the voxel D_i can be derived from the differential dose-volume histogram. Figure 2 and 3 show dose-volume histograms for patients 8 and 10 who had relatively large and small tumors, respectively. The DVH for patient 8 is interesting in that Monte Carlo calculations revealed a cold spot in the GTV, such that the Monte Carlo D100 was 9.3 Gy lower than that the TPS calculated. Figure 3 ???? >>> HERE

Figure 2.

Examples of dose distributions near the GTV in two patients. Panels A and B show the distributions for patient 4, who had a relatively large tumor; C and D show the distributions for patient 6, who had a small tumor. Panels A and C, are FF plans; B and D are FFF plans.

Figure 3.

Box plots of parameters characterizing dose distributions in the total lung. Red lines are the medians, blue boxes are interquartile ranges, and black dotted lines are ranges.

Normal tissue complication probability

To calculate the NTCP for the lung, we followed the method developed by Selvaraj et al. (19) who fit several models to radiation pneumonitis data from patients who received SBRT. The authors found that the Lyman-Kutcher-Burman model with a logistic local dose-effect relation for perfusion loss derived from single-photon emission computed tomography imaging data provided “modest improvement” over other models. In this model, the NTCP is calculated using the following equations:

$$\mathit{\text{NTCP}}=\frac{1}{\sqrt{2\pi }}{\int }_{-\infty }^{t}exp\left(-\frac{x^2}{2}\right)dx$$

$$t=\frac{EUD-T{D}_{50}}{m\cdot T{D}_{50}}$$

$$EUD=D_{50}{\left\{{\left[\sum _{i=1}^N\frac{1}{1+{\left(D_{50}/D_i\right)}^k}\cdot \frac{V_i}{V}\right]}^{-1}-1\right\}}^{-1/k}$$

In these equations, EUD is the equivalent uniform dose, TD₅₀ is the dose to an organ resulting in a 50% complication rate, m is the slope of the NTCP curve, D₅₀ is the local dose causing 50% damage, k characterizes the steepness of the local dose-effect curve, D_i is the dose to the i-th voxel, V_i is the voxel volume, and V is the total volume of the organ. The best fit values of the model parameters were: TD₅₀=24.9 Gy, m=0.38; D₅₀ =28.7 Gy, k=2.2.

Uncomplicated tumor control probability

The uncomplicated tumor control probability (UTCP) is the probability of achieving tumor control without complications. It is defined as UTCP=TCP×(1-NTCP).

Statistical analysis

Continuous variables are summarized by the median and range across subjects. All reported p-values comparing the FF and FFF beams were obtained from the Wilcoxon signed-rank test, using the paired values for FF and FFF for each subject. To assess the association of an anatomic feature with differences between FF and FFF beams, we performed univariate linear regression with the parameter ratio for FFF to FF as the response variable. p-values < 0.05 are considered to be significant. Analysis was performed in Matlab R2017b and R version 3.5.0.

Results and Discussion

Target coverage data are summarized in Table 2 and Figures 1 and 2. In all cases, the FFF beams achieved PTV coverage that was equivalent or improved compared with that achieved with the FF beams. The improvement was statistically significant for the D₉₈, D₉₅, D₉₀, HI, and UTCP. The FFF beams also improved the cohort’s median D₉₈ by 1.9%. In most cases, the TCP was close to 1. In the case with the lowest TCP, the FFF plan improved the TCP by 2.0%. Figure 1 shows box plots for the dosimetric indices characterizing the PTV dose distributions. FFF beams improved all median values (red lines), except that of D₁₀₀, which was essentially the same as that achieved with FF beams (the median FFF/FF ratio was 0.998). FFF beams similarly improved GTV coverage. The improvements in the D₉₅ and D₉₈ were significant. The cohort’s median D₉₈ was improved by 1.6%. Figure 2 shows a comparison of FF and FFF dose distributions near the target volume for patients 4 and 6, who had relatively large and small tumors, respectively. For patient 4, the 75- and 80-Gy isodoses in the FFF plan covered a much larger portion of the GTV than they did in the FF plan (Figures 2A and 2B). For patient 6, the 60- and 62-Gy FFF isodoses covered the superior part of the GTV better than the FF isodoses did (Figures 2C and 2D).

Table 2.

Target coverage data.

	FF		FFF
Parameter	Median	Range	Median	Range	p
GTV
D90, Gy	60.30	51.86, 78.27	60.99	51.65, 80.92	0.06
D95, Gy	59.73	51.71, 77.74	60.55	51.47, 80.50	0.05
D98, Gy	59.13	51.57, 77.24	60.08	51.40, 80.11	0.05
D100, Gy	57.67	51.14, 74.12	58.78	51.14, 77.07	> 0.1
PTV
D02, Gy	66.47	54.55, 83.69	65.56	52.95, 83.82	> 0.1
D50, Gy	58.69	51.64, 78.63	59.49	51.01, 80.10	0.06
D90, Gy	52.20	49.39, 72.43	53.20	49.07, 72.70	0.04
D95, Gy	50.94	48.72, 70.33	51.72	48.70, 70.50	< 0.01
D98, Gy	49.86	47.21, 67.19	50.79	48.26, 67.11	< 0.01
D100, Gy	46.00	37.50, 52.10	46.60	38.40, 54.10	> 0.1
HI	0.2151	0.09903, 0.3820	0.2080	0.09190, 0.3755	0.03
CI	1.163	0.2946, 1.939	1.148	0.3021, 1.556	> 0.1
TCP	1.000	0.8060, 1.000	1.000	0.8217, 1.000	> 0.1
UTCP	0.9585	0.7367, 0.9828	0.9604	0.7526, 0.9869	0.02

Abbreviations: FF, flattening filter; FFF, flattening filter-free; GTV, gross tumor volume; PTV, planning target volume; HI, homogeneity index; CI, conformity index; TCP, tumor control probability; UTCP, uncomplicated tumor control probability.

Figure 1.

Box plots of dosimetric indices characterizing PTV coverage. Red lines are the medians, blue boxes are interquartile ranges, black dotted lines are ranges, and red crosses are outliers.

Doses to OARs are summarized in Table 3 and Figures 3–6. In most cases, FFF beams lowered doses to OARs. Reductions in the mean lung dose, V₁₀, V₂₀, and V₃₀ were all statistically significant. Lower doses resulted in significantly lower NTCPs. The cohort’s median NTCP for FFF plans was 5.0% lower than that for FF plans. Box plots of the above indices for the total lung are shown in Figure 3 and clearly demonstrate the substantial lung sparing achieved with FFF beams. As for the ipsilateral lung, FFF plans significantly improved the mean lung dose, V₅, V₁₀, V₂₀, and V₃₀. The cohort’s median mean lung dose and V₂₀ in the FFF plans were 2.6% and 4.1% lower, respectively, than those in the FF plans. Figures 4 and 5 show the distributions of lung doses received by the lung in the FF and FFF plans for patients 4 and 6, respectively. In the FF plan in Figure 4, as compared with the FFF plan, the 10-Gy isodose extends farther into the contralateral lung, and the 10- and 20-Gy isodoses extend inferiorly farther into the mediastinum and ipsilateral lung. In the FF plan in Figure 5, as compared with the FFF plan, the 20-Gy isodose extends farther anteriorly and inferiorly into the normal lung. Figure 6 shows box plots of the maximum doses to other OARs (the esophagus, heart, and spinal cord) and the V₃₀ (cm³) for the chest wall. FFF plans lowered the maximum doses to OARs for most patients. The improvements were statistically significant for the heart and esophagus. For a few patients, the maximum dose to the heart with FFF plans was 20–60% higher than that with FF plans. For all these plans, the doses to the heart were much lower than the tolerance level; thus, we did not pursue further dose reduction.

Table 3.

Doses to organs at risk.

	FF		FFF
Parameter	Median	Range	Median	Range	p
Total lung
Dmean, Gy	4.998	1.512, 9.951	4.937	1.363, 9.924	< 0.01
V5, %	18.73	5.224, 49.63	17.46	4.942, 45.88	> 0.1
V10, %	13.06	4.374, 25.08	12.19	3.220, 23.70	< 0.01
V20, %	9.212	2.441, 16.92	8.570	1.077, 16.89	< 0.01
V30, %	4.568	1.190, 13.34	4.359	0.5664, 12.54	< 0.01
NTCP, %	4.149	1.717, 8.599	3.952	1.312, 8.406	< 0.01
Ipsilateral lung
Dmean, Gy	7.355	2.783, 20.16	7.172	2.005, 19.94	< 0.01
V5, %	26.13	13.30, 52.76	25.31	12.02, 51.54	< 0.01
V10, %	19.94	8.598, 47.91	18.70	5.458, 47.42	< 0.01
V20, %	15.62	4.054, 40.82	15.00	1.828, 40.74	< 0.01
V30, %	9.819	2.016, 32.19	9.319	0.9611, 30.25	< 0.01
Esophagus
Dmax, Gy	11.85	0.9020, 26.44	10.48	0.7100, 22.86	< 0.01
Heart
Dmax, Gy	2.675	0.1180, 57.84	2.819	0.09400, 55.48	0.04
V20, cm3	0	0, 80.42	0	0, 58.71	> 0.1
Spinal cord
Dmax, Gy	7.108	0.6120, 19.55	6.634	1.781, 15.65	0.09
Chest wall
V30, cm3	65.72	2.049, 966.1	61.45	0.3491, 979.9	> 0.1

Abbreviations: FF, flattening filter; FFF, flattening filter-free.

Figure 6.

Box plots of parameters characterizing doses received by organs at risk. Red lines are the medians, blue boxes are interquartile ranges, black dotted lines are ranges, and red crosses are outliers

Figure 4.

An example of dose distributions in the lung for patient 4. Panels A and B show FF and FFF plans, respectively (coronal plane view). The white dashed lines provide a reference for comparing the isodoses.

Figure 5.

An example of dose distributions in the lung for patient 6. Panels A and B show FF and FFF plans, respectively (sagittal plane view). The white dashed lines provide reference for comparing the isodoses.

Additional representations of dose distributions, convenient for comparing FF and FFF plans, are shown in Figures 7 and 8. These figures show the dose-volume histograms for patients 4 and 6. Achieving lower doses to the OARs was more difficult for the larger tumor (patient 4). In this case, we substantially lowered the maximum doses to all the OARs. For the spinal cord and esophagus, this led to larger volumes receiving low doses. In both patients, the FFF plans improved GTV coverage, especially for volumes above 90%, which translated into modestly increased doses to the parts of the GTV that received the lowest doses in the original FF plans. This GTV boost was not an explicit planning objective; rather, our main objective was to achieve equivalent PTV coverage between FF and FFF plans. This approach is well illustrated in Figure 7, which shows that achieving very similar PTV dose distributions in both plans led to higher GTV doses in the FFF plan. The differences in GTV coverage reflect the differences in the physics of FF and FFF beams: FFF beams have higher doses in the build-up region, (12) and near the beam’s central axis. The number of monitor units (MUs) per plan was on average 26% higher in FFF plans. We could lower this number, but that was not necessary, because the MU rate for the FFF beams (1400 MU/min) was much higher than that for the FF beams (600 MU/min), which resulted in a much lower BOT (Table 4). Also, higher MU numbers in the FFF plans were unlikely to result in higher out-of-field doses, because in the FFF configuration, the main source of scattering in the beam-line, the flattening filter, is absent.

Figure 7.

Dose-volume histogram for patient 4.

Figure 8.

Dose-volume histogram for patient 6.

Table 4.

Treatment delivery parameters.

	FF		FFF
Parameter	Median	Range	Median	Range	p
MUs	2072	948, 2929	2604	1268, 3775	< 0.01
BOT, min	3.5	1.6, 4.9	1.9	0.91, 2.7	< 0.01

Abbreviations: FF, flattening filter; FFF, flattening filter-free; MUs, monitor units, BOT, beam-on time.

We analyzed the data for potential associations between anatomic characteristics of the cohort and quantities describing the differences between FF and FFF treatment plans. We performed univariate linear regression analysis. The predictor variables were PTV volume, ipsilateral lung density, and chest wall thickness. The latter was calculated as the average wall thickness measured along the beam’s central axis for all beams in a plan. The response variables were the FFF/FF ratios of the following parameters: D₉₈, HI, CI, and TCP; mean dose, V₂₀, and NTCP for the total lung; maximum doses to the esophagus, heart, and the spinal cord; V₃₀ (cm³) for the chest wall; and total MUs and BOT per treatment fraction. Overall, we tested 3×13 predictor-response pairs, none of which showed strong evidence of association. Given our sample size, this negative finding may be due to limited power. A larger cohort is needed to establish associations conclusively.

Conclusions

By replacing FF beams with FFF beams of the same nominal energy in lung SBRT treatment plans, we were able to lower doses to OARs without compromising tumor coverage. Reduced doses to the ipsilateral lung were particularly consistent for all dose levels from 5 to 30 Gy. At the same time, target coverage was not compromised; rather, it actually improved in most cases. Hence, our findings provide evidence that the therapeutic ratio in lung SBRT can be improved by replacing FF beams with FFF beams. Nevertheless, in clinical practice, the choice of FFF over FF beams for individual patients should not be automatic; rather, it should be based on a comparison of FF and FFF treatment plans.